This invention relates to a method for delivery of pharmaceutically effective amounts of drugs and therapeutic ions. More particularly, this invention relates to a method of formulating a dosage form that will move drugs, pro-drugs or therapeutic ions in either cationic or anionic form between voltaic cell compartments of the human body, such as from the mouth into the naso-pharyngeal area or into the lung. This invention utilizes the naturally occurring concentration gradients in the form of concentration cells, which are constituents of the anatomy. This invention also relates to a dosage formulation designed in consideration of naturally occurring pH gradients, Le., Teorell-Meyer gradients, and a method of treatment by delivering a pharmaceutically effective amount of ions or drugs using the formulation designed in consideration of Teorell-Meyer gradients.
A new method for delivery of ions and drugs in ionic form is disclosed, including dosage forms designed according to the method of this invention. This dosage form represents an active dosage form that uses charge as a driving principle and is a complete departure from passive dosage forms, The dosage form will be able to move either cations or anions by taking advantage of the naturally occuring concentration gradients that exist in concentration xe2x80x9ccellsxe2x80x9d of the anatomy. One such concentration cell exists between from the mouth into the naso-pharyngeal area, trachea and possibly the lung. It is formed by the buccal cavity, the epiglottis and the naso-pharynx. By either raising or lowering the pH of the mouth to a suitable extent, by using a dosage form buffered at a correct pH, the ion or ionized drug or pro-drug will be moved electro-osmotically in accordance with Teorell-Meyer flux gradients.
The design of dosage forms according to this invention that are capable of moving ions, ionized drugs or carrier ions from one physiological compartment to another (defining a xe2x80x9ccellxe2x80x9d), in a pH dependent manner, derives mathematically from the Teorell-Meyer Theory. See, Teorell, T., Discussions Faraday Soc., 1956, 21(9), 305-369. The derivation according to this invention predicts that a dosage form buffered at the correct pH will be able to move either the desired positive or negative ions from compartment A to compartment B in an pH dependent osmo-electrophoretic manner, provided a flux gradient exists between two and possibly more compartments. Examples of such compartments are: mouthxe2x80x94nose; vaginaxe2x80x94uterousxe2x80x94Fallopian tubes; outer and inner ear; and many others that are described in the work of Nordenstrom, B. E., Biologically Closed Electrical Systems: Clinical, Experimental and Theoretical Evidence of an Additional Circulatory System; Stockholm, Nordic Medical Publications, 1983, and Evans, E. E., Schentag J. J., Jusko W. J. eds, Applied Pharmacoldnetics: Principles of Therapeutic Drug Monitoring, 3rd ed, Vancouver, Wash., 1992, which are incorporated herein by reference.
Dosage forms designed according to the method of this invention are ideal for reaching one compartment from another and provide more direct application of drug to a target area than most conventional dosage forms, particularly those dosage forms that rely on systemic circulation. This allows the dosage form to actually contain a lower dosage of drug, since a higher percentage of drug is delivered to the target area. The drug can also be delivered directly to the target area as needed. Under some conditions where drug substances are transported through membranes, the drugs may become concentrated in the target tissues. In addition, fewer side effects should be expected from dosage forms according to this invention than from systemic dosage forms.
This dosage form will obviate conventional delivery systems such as nasal sprays. It is superior to such systems because it can be targeted to specific tissues in the body according to the prevailing Donnan Equilibrium of that tissue. These equilibria can be mapped. A Donnan Equilibrium is an area of fixed charge, held in place by the tertiary and quaternary struture of the constituent proteins in the target tissue. Thus a drug can be guided to a specific tisssue and leave another relatively or entirely untouched.
This method is applicable to almost any therapeutic agent that is capable of existing in ionized form, although those agents of lower molecular weight or size will be transported faster and are therefore preferred. Non-ionic agents require an ionizable carrier, which must meet the further requirements of providing for favorable release of the drug at the target site as well as being metabolizable or otherwise easily eliminated physiologically.
It is an object of the present invention to provide for the design of pharmaceutical compositions which provide better, non-systemic delivery of drugs from a repository compartment of the human body to an adjacent compartment by utilization of the naturally occuring pH gradients between, the two compartments.
It is another object of the present invention to provide a pharmaceutical composition designed in consideration of the Teorell-Meyer gradient for the delivery of a drug from the mouth to the naso-pharyngeal area.
It is a further object of the invention to provide a method of non-systemic administration of an active drug or pro-drug to a patient.
Additional objects of the invention will become evident by study of the detailed description of preferred embodiments of the invention.
The above and other objects of the invention are provided by a method for formulating the composition of drug dosage forms which will deliver active drugs from a body compartment or organ in which it is placed, i.e., a repository compartment or organ, to a recipient compartment based on the Teorell-Meyer gradient of differing pHs between the two compartments. The method entails identifying both the repository and recipient compartments and determing the pH of each compartment, and is applicable to compartments that are adjacent or contiguous, or that are separated only by a thin membrane. In addition, the repository compartment is in the form of a cavity large enough to contain the desired doage form. Examples of such contiguous compartments include; the mouth and naso-pharynx, mouth-trachea-bronchioles and bronchi, and possibly lung, the surface of the eye, the sclera, the cornea, the anterior chamber, iris, posterior chamber, retina and possibly the optic nerve, the vagina-uterous-fallopian tubes and possibly the ovary, the middle and inner ear, epidural space-meninges-brain, to name a few. The method is also applicable to solid organs as well, such as the eye, liver and prostate. This invention is not limited in scope to the few compartment systems or organs listed here, but is meant to include any such compartment system as meets the basic requirements described herein. Such compartment systems may also be identified in Nordenstrom or Evans. Also, it is expected that a medical or pharmaceutical practitioner of ordinary skill in the art would appreciate the full range of applicability of the within invention.
Selection of contiguous repository/recipient compartment systems to which this invention would apply is dictated largely by pH differences between the two compartments, although other factors may be present as well. Generally, a difference of at least 0.1 pH units between the compartments is necessary, although the larger the pH difference the faster the active drug will be transported. A pH difference of 2.0 pH units is usually preferred, but a larger difference is possible according to the tolerance of the tissues. Thus, each dosage form has its own limits based on the practical pH difference between the compartments and each dosage form should be calculated according to the desired transport time that makes sense for the system. In the preferred embodiment of the mouthxe2x80x94nose system, the transport time should be within the twenty minutes needed to dissolve a typical lozenge. The pH difference, therfore, need only be about 0.4. On the other hand, for a suppository, a pH difference of 0.1 producing a transport time of about an hour and fifteen minutes would be acceptable.
Once the compartment system is identified the active drug or pro-drug must be selected. Transfer by the within method is applicable to almost any drug that is in anionic, cationic or ionizable form. Ionic drugs should be hydrated. Non-ionic drugs may also be used as they can be released from an ionizable carrier such as cyclic carbohydrates and cyclodextrans. The speed of travel of the drug depends on the charge, the atomic or molecular diameter, the molecular weight and the viscosity of the medium in which it travels. The dosage form will move any ionic substance with a molecular weight of up to thousands of Daltons.
In the case of a cationic (positively charged) or acid drug, the repository compartment must have an induced pH substantially lower that the recipient compartment. Conversely, for an anionic (negatively charged) or basic drug the repository compartment must have an induced pH higher than the recipient compartment. Thus, the selection of the buffering system for the dosage form is highly significant. The range of buffers employed correspond to the range of pHs found in the human body, the lowest pH presently known is that of the stomach which is about pH 0.1, the highest pH presently known is about 9.0 and is found in the lower intestine. The buffer or buffer system must last long enough for consumption of the entire dose for complete drug transport to occur. For example, for a typical lozenge of 5 gm, about 20 minutes is necessary.
While the buffers selected must create a pH differential between; the compartments of ideally 2.0 pH units or more to cause rapid drug movement, greater or smaller pH differences are not beyond the scope of this invention. However, when selecting the buffer physiological considerations must also be taken into account. That is, the amount of pH difference between the dosage buffer and the repository compartment that the tissue of that compartment will tolerate.
For the purpose of this invention, the 20 physiologically accepted amino acids and their congeners (e.g., orotic acid, carnitine, ornitine) are generally preferred. The buffers systems usually contain at least two components: a salt and its correlative acid, or base. Buffers may be single compounds in certain cases, such as solutions of amino acids, Tris(copyright), and other compounds containing both acid and basic groups on the same molecule. A buffering system may be complex, containing several components. It may also contain non-related salts and amino acids or similar zwitterionic compounds.
The buffering agent should be able to reliably buffer at the chosen pH, which may be anywhere within the physiological range, so as to preferably maintain a difference of at least 2 pH units between the repository and recipient compartments, according to tissue tolerance, for the preferred embodiment of the invention, to exert substantial buffering capacity within this range. Preferred buffering agents are the amino acids, hydrogen and dihydrogen phosphates, such as sodium dihydrogen phosphate and mixtures of sodium dihydrogen phosphate with sodium hydrogen phosphate, calcium tetrahydrogen phosphate, citric acid and mixtures of citric acid and its monosodium salt, fumaric acid and its monosodium salt, adipic acid and its monosodium salt, tartaric acid and its monosodium salt, ascorbic acid and its monosodium salt, glutamic acid, aspartic acid, betaine hydrochloride, hydrochlorides of amino acids, such as arginine monohydrochloride and glutamic acid hydrochloride and saccharic acid, and other suitable GRAS ingredients herein incorporated by reference.
According to the invention there is provided a method of designing the dosage form of the composition according to the invention, said method comprising the following steps:
selecting the recipient compartment and the associated repository compartment for placement of the drug dosage form,
determining the pHs of both the repository and recipient body compartments,
identifying the ion, drug or pro-drug to be used in treatment of the recipient compartment, including the ionic characteristics of the drug and its molecular size and shape,
selecting a buffering system that will provide satisfactorily lasting buffering effect in the repository compartment of generally at least 0.1 pH units and preferrably 2.0 pH units or more lower than the recipient compartment if the drug is cationic (overall positive charge), or at least 0.1 pH units and preferrably 2.0 pH units or more higher than the recipient compartment if the drug is anionic (overall negative charge), and
admixing the ion, drug or pro-drug together with the components of the selected buffering system, at least one pharmaceutically acceptable carrier, if needed for the transport of a non-ionic molecule, a pharmaceutically appropriated form base and inert ingredients into a desired dosage form such as a lozenge, tablet, capsule, emulsion, injectable emulsion, implantable seed, physiological insert, ophthalmic insert, absorbable sponges, skin patches, pharmaceutical candles, bougies, troches, pastilles and medicated confections.
In another application of the within invention it is desirable to assess the total drug delivery time between the compartments of a given system in order to determine the necessary pH differences between the compartments. Selecting an appropriate drug delivery time and knowing the pH of the recipient compartment, the pH of the repository compartment necessary for total drug transport can be determined. Accordingly, a buffer system designed to produce this pH can be selected.
The invention further relates to a method for administration of a single dose of a dosage form designed according to the above method to a patient comprising administering orally to the patient a lozenge, capsule, tablet containing a pharmacologically effective amount of an ion, drug or pro-drug in the dosage form created according to this invention.